human psychopharmacology

Hum. Psychopharmacol Clin Exp 2009; 24: 515523. Published online 19 August 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.1048

REVIEW ARTICLE

Cannabis and anxiety: a critical review of the evidence

Jose Alexandre Crippa1,2y, Antonio Waldo Zuardi1x, Rocio Martn-Santos2,3, Sagnik Bhattacharyya2, Zerrin Atakan2, Philip McGuire2 and Paolo Fusar-Poli2,4*
1

Department of Neurosciences and Behavior, Division of Psychiatry, Ribeirao Preto School of Medicine, University of Sao Paulo (USP-RP) and INCT Translational Medicine, Brazil 2 Department of Psychological Medicine, Section of Neuroimaging, Institute of Psychiatry, Kings College London, London, UK 3 Neuropsychopharmacology Group, IMIM-Hospital del Mar and Department of Psychiatry; Institute of Neuroscience, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Spain 4 Department of Health Sciences, Section of Psychiatry, University of Pavia, Pavia, Italy

Background Anxiety reactions and panic attacks are the acute symptoms most frequently associated with cannabis use. Understanding the relationship between cannabis and anxiety may clarify the mechanism of action of cannabis and the pathophysiology of anxiety. Aims of the present study were to review the nature of the relationship between cannabis use and anxiety, as well as the possible clinical, diagnostic and causal implications. Method Systematic review of the Medline, PsycLIT and EMBASE literature. Results Frequent cannabis users consistently have a high prevalence of anxiety disorders and patients with anxiety disorders have relatively high rates of cannabis use. However, it is unclear if cannabis use increases the risk of developing long-lasting anxiety disorders. Many hypotheses have been proposed in an attempt to explain these relationships, including neurobiological, environmental and social inuences. Conclusions The precise relationship between cannabis use and anxiety has yet to be established. Research is needed to fully clarify the mechanisms of such the association. Copyright # 2009 John Wiley & Sons, Ltd. key words Cannabis sativa; tetrahydrocannabinol; cannabidiol; anxiety; psychosis

INTRODUCTION Association between Cannabis sativa and psychopathologic conditions have existed since before the Christian era (Zuardi et al., 2006). However, while there has been considerable interest in the relationship between cannabis use and psychosis (Arseneault et al., 2004), the association between cannabis and other psychiatric disorders, particularly anxiety, has received relatively little attention. One of the possible reasons is that patients with cannabis-associated anxiety do not attract as much attention from clinical services as those

* Correspondence to: P. Fusar-Poli, Neuroimaging Section, PO67 Department of Psychological Medicine, Institute of Psychiatry, De Crespigny Park 103, Kings College London, SE5 8AF London, UK. Tel.: 39 349 6053229. E-mail: p.fusar@libero.it y Professor. x Full Professor and Head of the Department of Neurosciences and Behavior. Full Professor and Head of the Neuroimaging Section.

with psychosis. As the drug is illegal in most countries, patients with anxiety may be reluctant to reveal cannabis use (Degenhardt et al., 2003). Moreover, anxiety may be induced by cannabis use or may be a symptom of withdrawal in the context of cannabis dependence, the existence of which has been a matter of debate (Budney et al., 2004; Rosenberg and Anthony, 2001). Thus this may result in confusion about the diagnosis of anxiety symptoms reported in the context of recent cannabis use. Understanding the association between cannabis use and anxiety may clarify both the mechanism of action of cannabis and the pathophysiology of anxiety. Given that cannabis is the most widely used illicit drug in the world (Murray et al., 2007) and anxiety is the most prevalent mental disorder (Kessler et al., 2005), these are issues of great interest. The purpose of this critical review was to investigate the nature of relationship between cannabis use and anxiety, as well as the possible clinical, diagnostic and causal implications.
Received 28 March 2009 Accepted 17 June 2009

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METHODS We performed systematic searches of the following electronic databases to identify all studies published in the English language from their inception to August 2008: Medline, PsycLIT and EMBASE. The search terms used were CANNABIS, MARIJUANA, THC, TETRAHYDROCANNABINOL, DELTA-9TETRAHYDROCANNABINOL, CANNABINOIDS and ANXIETY, PANIC, PHOBIA and STRESS. Where Medical Subject Heading terms were available, they were enlarged and incorporated. The reference lists of eligible papers were checked for additional relevant studies. RESULTS Vulnerability and acute effect Cannabis can cause an acute and short-lasting episode of anxiety, which often resembles a panic attack, in those who are not habitual users. When taken in high doses [(>5 mg oral D9-tetrahydrocannabinol (D9THC) for a man of average weight], cannabis can cause intense fear and anxiety. With higher doses, panic and phobic attacks may occur (Hall and Solowij, 1998; Roy-Byrne and Uhde, 1988; Thomas, 1993; Tournier et al., 2003; Tunving, 1987). About 2030% of users show brief acute anxiety reactions after smoking the drug (Hollister, 1986; Thomas, 1996). Such symptoms usually occur when the drug is used at high doses and are more common in drug-nave subjects and in novel or stressful environmental situations (Manzanares et al., 2004). This has been consistently described in experimental studies in man (DSouza et al., 2004; Gregg et al., 1976; Naliboff et al., 1976; Zuardi et al., 1982) and in many case reports (Deas et al., 2000; Moran, 1986). Such manifestations mostly resemble those described in patients with anxiety disorders. Anxiety reactions and panic attacks appear to result in aversion to further use of the drug, as these symptoms are one of the most common reasons given for the cessation of cannabis use. These individuals are also less likely to become regular users (Thomas, 1996). Similarly, cannabis can exacerbate existing anxiety symptoms, precipitate recurrence of an acute episode and counteract the effects of anxiolytic medication (Szuster et al., 1988). Table 1 summarises the factors associated with the risk of anxiety induced by cannabis use. Table 2 summarizes the experimental studies involving acute administration of cannabinoids on human anxiety.
Copyright # 2009 John Wiley & Sons, Ltd.

Table 1. Factors associated with the risk of anxiety induced by cannabis use Individual and genetic vulnerability Personality traits Gender Frequency of use Dose and quantity consumed Proportions and concentration of cannabinoidsa History of previous episode Presence of anxiety disorders/symptoms Basal anxiety levels Abstinence states Environment and context of use
a

Especially of D9-tetrahydrocannabinol (D9-THC) and cannabidiol (CBD).

In contrast, long-term users typically report that cannabis use is associated with a reduction in anxiety. Relaxation and relief from tension remain the most common effects of using cannabis and the most common reasons for using the drug (Boys et al., 1999; Hathaway, 2003; Reilly et al., 1998). Evidence of the association between anxiety and cannabis use Cannabis use and anxiety symptoms. Frequent cannabis users appear to have higher levels of anxiety than non-users, without these necessarily representing an anxiety disorder. In a study with people who regularly used cannabis for at least 10 years, 21% of the subjects had high levels of anxiety (Reilly et al., 1998). In another study involving draftees to the Italian army, it was found that the severity of anxiety symptoms increased progressively with increasing cannabis use and higher levels of anxiety were observed in those who reported abuse or dependence on the drug (Troisi et al., 1998). A recent study conrmed that cannabis dependence in adolescents is related to increased psychological distress and anxiety levels (Dorard et al., 2008). A similar result was found in two indigenous communities in the northern territory of Australia (Clough et al., 2005). The authors found that the severity of symptoms within the anxiety-dependency cluster in cannabis users increased as their level of cannabis use increased (Clough et al., 2005). This seems to be particularly evident among women, as observed in cannabis-dependent individuals arrested for marijuana-related offending behaviour (Feeney et al., 2005). State anxiety level was also one of the main predictors of increased severity of cannabis use (Spalletta et al., 2007), while the marijuana use increased the risk for anxiety symptoms and catastrophic thinking (Zvolensky et al., 2006b). Furthermore, a recent
Hum. Psychopharmacol Clin Exp 2009; 24: 515523. DOI: 10.1002/hup

cannabis and anxiety

Table 2. Acute effects of cannabinoids in experimental studies on human anxiety Study Anxiogenic effect Karniol et al. (1974) Gregg et al. (1976) Naliboff et al. (1976) Peters et al. (1976) Zuardi et al. (1982) DSouza et al. (2004) Ilan et al. (2005) Fusar-Poli et al. (2009) No effect Glass et al. (1980) Ilan et al. (2005) Anxiolytic effect Karniol et al. (1974) Zuardi et al. (1982) Zuardi et al. (1993) Crippa et al. (2004) Fusar-Poli et al. (2009)
a b

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Subjects (N) 40 10 15 10 8 22 23 15 4 23 40 8 10 10 15

Cannabinoid D9-THC D9-THC D9-THC D9-THC D9-THC D9-THC D9-THC D9-THC Nabilone D9-THC CBD CBD CBD CBD CBD

Route Oral Intravenous Inhalatory (cigarettes) Oral Oral Intravenous Inhalatory (cigarettes) Oral Oral Inhalatory (cigarettes) Oral Oral Oral Oral Oral

Dose 30 mg 0.022 and 0.044 mg/kg 14 mg 0.2, 0.4 and 0.6 mg/kg 0.5 mg/kg 2.5 and 5 mg 3.6% 10 mg 1 and 4 mg 1.8% 15, 30 and 60 mg 1 mg/kg 300 mg 400 mg 600 mg

Results Reported anxiety and panic Intensify scores of STAIa during oral surgery Intensify FBFb and HRc means during arithmetic task Increased scores of tension items of SDEQd Increased scores of STAIa Increased anxious scores of VASe Increased anxious scores of VASe Increased scores of STAIa No signicant effect on POMSf anxiety No signicant effect on VASe anxious scores Reported less anxiety and panic induced by D9-THC Decreased STAIa scores elevation induced by D9-THC Decreased VAS factor anxiety scores after public speaking Decreased VAS factor anxiety scores before SPECTg procedure Decreased skin conductance uctuation in task with fearful face

State-Trait Anxiety Inventory. Forearm Blood Flow. c Heart Rate. d Subjective Drug Effects Questionnaire. e Visual Analog Scale. f Prole of Mood States. g Single-Photon Emission Computed Tomography.

study in university students indicated that the association between cannabis use and anxiety symptoms may trigger risky and suicidal behaviours (Innamorati et al., 2008). Comorbidity between cannabis use and anxiety disorders. Comorbidity is dened as the overlap of two or more psychiatric disorders. In general, few epidemiologic studies have evaluated the comorbidity of cannabis use and anxiety in the general population. These studies have suggested that chronic cannabis use is associated with a higher prevalence of comorbidity with anxiety disorders, especially panic and social anxiety disorders. In a study with 18-year-old New Zealanders, it was reported that those who had consumed cannabis ten times or more between the ages of 15 and 16 had a higher prevalence of anxiety disorders (31%) more than twofold that of individuals who had never used the drug (Fergusson and Horwood, 1997). Analysis of data obtained in the National Comorbidity Survey (NCS) suggested that the probability of diagnosing anxiety or mood disorder (either in the
Copyright # 2009 John Wiley & Sons, Ltd.

previous month or throughout life) was approximately doubled in subjects with cannabis dependence. Thus, subjects with cannabis dependence had a higher comorbidity with anxiety disorders (between 6.9 and 29%, depending on the disorder) than those without cannabis dependence. It was also observed that a considerable number of subjects developed anxiety disorders before the rst symptoms of cannabis dependence suggesting that some of them may have been using cannabis as a self-prescribed anxiolytic medication (Agosti et al., 2002). In line with this hypothesis a recent study observed that social anxiety disorder is an independent risk factor for cannabis dependence (Buckner et al., 2008). In a study by the Australian National Survey of Mental Health and Well-Being, in subjects aged over 18, it was veried that 17% of individuals with cannabis dependence showed anxiety disorders compared to only 5% of non-users. Nonetheless, cannabis use did not appear to be related to anxiety when the data was adjusted for demographic characteristics, other substance use and personality traits (Degenhardt et al., 2001).
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Subsequently, it was also observed that agoraphobia is signicantly associated with higher predisposition to cannabis use, regardless of anxiety condition and other confounding factors. However, the authors did not nd evidence of anxiolytic or anxiogenic effects in daily cannabis use (Tournier et al., 2003). A lifetime history of cannabis dependence has been signicantly related to an increased risk of panic attacks. In addition, the authors of this study found that the age of onset of panic attacks was signicantly earlier among the subjects with both conditions than for individuals with panic attack with no cannabis use (Zvolensky et al., 2006a). Another recent prospective longitudinal study investigating 1709 adolescents showed that cannabis use and dependence were signicantly associated with an increased risk for the development of panic attacks and panic disorder (Zvolensky et al., 2008). As occurs with other illicit drugs, individuals with anxiety disorder have a stronger chance of presenting with cannabis dependence or abuse throughout life and vice versa. For example, Strike et al. (2003) veried that 13% of individuals dependent on cannabis who sought treatment had a history of previous anxiety disorder. Similarly, Swadi and Bobier (2003) veried that 63% of patients hospitalized with an anxiety disorder presented with a comorbid substance abuse disorder, especially cannabis. On the other hand, suffering from an anxiety disorder seems to be one of the most important reasons for cannabis users to seek psychiatric treatment. Anxiety as manifestation of cannabis abstinence. Anxiety is one of the main manifestations of the cannabis withdrawal syndrome (Bonn-Miller et al., 2007; Haney, 2005). Its onset is typically between the second and sixth day and lasts from 4 to 14 days (Budney et al., 2004). The severity and duration of these effects are comparable to those of tobacco and other withdrawal syndromes, which commonly contribute to the development of dependence and difculty in abstinence (Vandrey et al., 2005). However, the existence of a cannabis withdrawal syndrome is not universally accepted and it is still not included in the DSM-IV (American Psychiatric Association, 1994). Bupropion and Divalproex have not proven effective in treating cannabis withdrawal symptoms (Haney et al., 2001, 2004). In another single dose study, Nefazodone effectively decreased some marijuana withdrawal symptoms, but did not affect the majority of the symptoms (Haney et al., 2003). The most promising demonstration of suppression of symptoms of cannabis withdrawal was observed through the use
Copyright # 2009 John Wiley & Sons, Ltd.

of oral D9-THC (from 30 to 90 mg/day), which decreased both symptoms and cravings. At this dose it did not produce intoxication and induced only minimal adverse effects (Budney et al., 2007; Haney et al., 2004). Cannabis use and risk for developing anxiety disorders. While there is little doubt that cannabis use can cause anxiety symptoms, it is less clear that it can increase the risk of developing anxiety disorders which persist after the cessation of use. Several cases of agoraphobia (Moran, 1986) and panic disorder (Dannon et al., 2004; Langs et al., 1997) induced by cannabis use have been previously described. Some authors have also speculated that cannabis use may be associated with enduring anxiety symptoms, as these clinical observations parallel data from animal studies (OShea et al., 2004, 2006). It was observed that frequent cannabis use in adolescent females doubled the chances of their subsequently presenting with anxiety and depressive conditions, with daily cannabis use increasing the risk fourfold (Patton et al., 2002). As depression did not predict higher cannabis use in later life, this seems unlikely to reect self-medication with cannabis for these symptoms; consistent with an earlier report (McGee et al., 2000). These ndings have been replicated by a recent study which followed up a cohort of 3239 Australian young adults from birth to the age of 21 years. After controlling for confounding factors, those who started using cannabis before the age of 15 years and used it frequently at 21 years were more likely to report symptoms of an anxiety disorder in early adulthood (Hayatbakhsh et al., 2007). However, contrasting results were observed in a large longitudinal study that focused on the vulnerability factors in adolescent substance use (Windle and Wiesner, 2004). These contrasting ndings were further supported by a recent study which investigated whether cannabis use predicted the rst incidence of mood and anxiety disorders in 6000 adults during a 3-year follow-up period. Use of cannabis at baseline predicted a modest increase in the risk of a rst episode of major depression and a stronger increase in the risk of a rst episode of bipolar disorder. Although there was an association noted between cannabis use and anxiety disorders, it did not survive after controlling for confounding factors (Van Laar et al., 2007). Given that the relationship between anxiety symptoms and cannabis use in individuals with comorbid cannabis use and anxiety disorders is clinically complex and they normally continue to use the drug,
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there is a growing concern that they may be difcult to treat. Thus, Dannon et al. (2004) studied several patients with panic disorder, the onset of which began 48 h after cannabis use. The authors found that such cases were responsive to pharmacological treatment with paroxetine. However, it was recently observed that the combination of cognitive-behavioural therapy and pharmacotherapy was not effective for the treatment of panic or social phobia symptoms among occasional cannabis users (Bricker et al., 2007). Nonetheless, the existence of a causal relationship between cannabis use and long-term anxiety disorders remains dubious (Gilder et al., 2006; Windle and Wiesner, 2004). For instance, if cannabis use were to have been responsible for the precipitation of anxiety disorders, one would have expected an increase in the number of people presenting with these disorders in recent years, as the prevalence and extent of cannabis use has increased in recent times (Boydell et al., 2006; Iversen, 2003). Possible explanations for the association between anxiety and cannabis use In spite of some studies suggesting that there exists an association between cannabis use and high levels of anxiety, personality traits and anxiety disorders, they are not informative regarding the parameters of such association (Compton et al., 2000; McGee et al., 2000; Meser et al., 1998). Many hypotheses have been proposed in an attempt to explain this relationship. How could cannabis modulate anxiety?. Using cannabis could precipitate acute anxiety in two ways:
(i) The main active psychoactive ingredient in cannabis, D9-THC, could elicit anxiety symptoms through its effects on serotonin, noradrenalin (Braida et al., 2007; Degenhardt et al., 2003; Muntoni et al., 2006) GABA and glutamate (Pertwee, 2008). Although there is relatively scarce information about the interactions between the serotonergic and the endocannabinoid systems, there is some emerging evidence of a complex interplay between the two systems, the full extent of which is not yet clear (Braida et al., 2007; Viveros et al., 2005). Recent animal studies have conrmed that cannabidiol (CBD), the non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects may do so by having an effect on 5HT1A receptors (Braida et al., 2007; Campos and Guimaraes, 2008; Patel and Hillard, 2006; Witkin et al., 2005). (ii) Acute intoxication could also lead to anxiety secondary to impaired cognitive functioning and the clouding of consciousness.
Copyright # 2009 John Wiley & Sons, Ltd.

In mice and rats, administration of D9-THC causes stronger aversion to the open arms on the elevated plusmaze, similar to the effect of anxiogenic agents (Moreira and Lutz, 2008; Onaivi et al., 1990). Conversely, CBD, when administered with THC at therapeutically relevant ratios, ameliorate aversive effects associated with initial use of THC alone (Vann et al., 2008). Cannabis use could also lead to persisting anxiety disorders through an enduring deregulation of the endocannabinoid systems (anandamide), particularly in genetically vulnerable individuals (Witkin et al., 2005). Additionally, emerging data from human and animal perinatal exposure studies suggest neurodevelopmental or hormonal effects of cannabis upon subsequent anxiety and mood states, especially among adolescents (Sundram, 2006). Similarly, there could be other indirect relationships. For instance, chronic cannabis use beginning at a young age could increase the possibility of lower educational attainment levels due to dropouts or failure. This could limit employment prospects and subsequent unemployment could increase stress resulting in anxiety symptoms/disorders (Lynskey et al., 2002). Other psychosocial mechanisms, such as the adoption of a countercultural lifestyle, may also underlie the association (Patton et al., 2002). Moreover, in respect to panic disorder, it was postulated that cannabis withdrawal symptoms might increase the chance of panic-relevant learning, as individuals experience more intense interoceptive sensations and misinterpret them as personally dangerous, potentially leading to a panic attack (Zvolensky et al., 2006a, 2008). Anxiety leads to cannabis consumption. Prospective studies indicated that anxiety disorders in adolescence may predict later cannabis use and cannabis use disorder (Wittchen et al., 2007). The most popular explanation for this relationship is that subjects with high levels of anxiety and patients with anxiety disorders use cannabis as a form of self-medication (Arendt et al., 2007; Stewart et al., 1997). Supporting this idea, many subjects report using cannabis to relax, to cope with stress and as a way to reduce anxiety (Bonn-Miller et al., 2007; Boys et al., 1999; Buckner et al., 2008; Hathaway, 2003; Ogborne et al., 2000; Reilly et al., 1998). Moreover, the expectation that cannabis will reduce anxiety has been associated with its use in non-clinical undergraduates as well as in psychotic subjects (Schoeld et al., 2006) and in their relatives (Smith et al., 2008) as well as in individuals with HIV/AIDS (Prentiss et al., 2004; Woolridge et al., 2005), among other conditions.
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This hypothesis has been partially supported by data from a study in which the anxiolytic effects of Nabilone (3 mg/day), a synthetic cannabinoid derived from D9-THC, were evaluated. In a double-blind, placebo-controlled study, patients with anxiety disorders demonstrated reduced symptoms after 28 days of treatment with nabilone (Fabre and McLendon, 1981). Ilaria et al. (1981) in a placebo-controlled crossstudy, also veried the ability of nabilone (25 mg/day) to reduce symptoms of anxious patients as assessed by the Hamilton Anxiety Scale. Nevertheless, it is prudent to discourage using cannabis, particularly in patients with psychosis or anxiety disorders. Common factors increase risk for anxiety as well as for cannabis use. In this model, both anxiety disorder and cannabis use could have common etiopathological causes. Such factors include biological, neurodevelopmental, environmental and social inuences, as well as personality traits or a combination of all of them (Chabrol et al., 2005; Lynskey et al., 2002; Windle and Wiesner, 2004). For example, animal studies have indicated that maternally deprived adolescent rodents have altered responses to cannabinoid compounds (Marco et al., 2008). Other investigations have suggested that perinatal THC exposure induced an anxiogenic-like prole in the adult offspring tested in the elevated plus-maze test (Trezza et al., 2008). Similarly, factors associated with substance abuse in patients with anxiety disorders appear to be similar to those associated with substance abuse in the general population (i.e. cost, availability, boredom, impulsiveness, seeking sensation and facility of social interaction, among others) (Bonn-Miller et al., 2007; Sbrana et al., 2005). For instance, peer inuence may have a role in problematic cannabis use even among individuals with social anxiety disorder (Buckner et al., 2006). Cannabis use by patients with anxiety disorders could also reect a specic genetic vulnerability. For instance, both psychotic subjects and their relatives have been shown to present high rates of cannabis use (Smith et al., 2008). Alternatively, genetic factors could increase risk for anxiety in cannabis users, especially male subjects (Schoeld et al., 2006). CONCLUSION It is paradoxical that while individuals report reduced anxiety as the motivation for using cannabis, yet acute anxiety is the most common adverse effect of cannabis use. These conicting statements may be reconciled through the observation that the effects of cannabis on
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anxiety appear to be dose-dependent. Thus, low doses of the cannabinoid receptor agonists, nabilone (Onaivi et al., 1990), CP 55.940 (Marco et al., 2008) and D9THC (Berrendero and Maldonado, 2002) have anxiolytic-like effects in laboratory rodents, whereas higher doses produce anxiogenic behaviour and activate the hypotalamicpituitaryadrenocortical axis (Berrendero and Maldonado, 2002; Giuliani et al., 2000; Manzanares et al., 1999; Viveros et al., 2005). Anxiety induced by D9-THC is facilitated by exposure to novel or stressful environments that appears to be mediated by the central amygdala (Patel et al., 2005; Phan et al., 2008). Although D9-THC is commonly regarded as the main factor responsible for the psychoactive effects of cannabis, several reports have demonstrated that other components of the plant inuence its pharmacological activity. One of these compounds is CBD, which may constitute up to 40% of cannabis extracts and is not associated with the psychological and cognitive effects usually associated with cannabis use in humans. In fact, studies in laboratory animals and in humans have demonstrated that CBD has anxiolytic properties (Fusar-Poli et al., 2009); in contrast with the anxiogenic effects of D9-THC in high doses (Zuardi et al., 1982). Plant samples vary in the proportions and relative concentrations of THC and CBD. These depend on soil and weather conditions, where the plant grew, the part of the plant which provided the sample (stems have more CBD, leaves and owers have more D9-THC); and other factors. The present review demonstrates that cannabis use and anxiety symptoms/disorders often co-occur. Several factors may explain this association, but further research is needed to clarify the mechanisms by which cannabis use may cause acute anxiety and long-lasting anxiety disorders. Longitudinal studies may be helpful in obtaining better understanding of environmental, social, neurobiological and other confounding factors. Through such studies, more specic and efcacious treatments and primary prevention strategies could be more easily developed.

CLINICAL IMPLICATIONS
 Anxiety is the acute symptom most frequently associated with cannabis use, particularly at high doses. Acute anxiety following cannabis use is more common in drug-nave subjects and when the drug is taken in novel or stressful environments.  Cannabis use alone does not appear to be sufcient or necessary for the development of long-term anxiety but
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cannabis and anxiety may be a risk factor that operates in conjunction with other vulnerability factors.  Chronic cannabis use is associated with higher prevalence of anxiety disorders and vice versa. In addition, acute anxiety can be a feature of a cannabis withdrawal syndrome. LIMITATIONS  While several environmental, social and neurobiological factors have been implicated in the association between cannabis use and anxiety, the precise basis of the relationship remains unclear.  Only a few prospective studies have been conducted and these have relied on self-reported measures of cannabis use.  More longitudinal studies are required to estimate the long-term impact of cannabis use on anxiety and anxiety disorders. ACKNOWLEDGEMENTS Research was supported in part by FAEPA and FAPESP fellowships (grant 02/13197-2). J. A. C. and A. W. Z. are recipients of a CNPq Productivity fellowship. Studies actually conducted by the authors are sponsored by THCPharmaceuticals, Germany and STI, UK, which provided cannabidiol. A former study was sponsored by GW Pharmaceuticals, UK. S. B. is supported by a Joint Priory/MRC Clincal Research training fellowship from the Medical Research Council (MRC), UK. P. F. P. has no conict of interests to declare. This study was designed by Jose Alex andre Crippa and Antonio W. Zuardi. Jose Alexandre Crippa and Paolo Fusar-Poli were responsible for literature search. Jose Alexandre Crippa takes responsibility for the integrity of the data and the accuracy of the references. Philip McGuire, Zerrin Atakan, Sagnik Bhattacharyya and Rocio Martin-Santos have helped with interpretation of the results. All authors have agreed to the submission in this form and we do not have any interests that might be interpreted as inuencing its content.

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Hum. Psychopharmacol Clin Exp 2009; 24: 515523. DOI: 10.1002/hup